2-241073314-G-T

Variant names:

• chr2-241073314-G-T
• rs6721345
• NM_001080437.3:c.3866G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080437.3(SNED1):​c.3866G>T​(p.Arg1289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,421,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1289Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SNED1 NM_001080437.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.414
• Publications: 12 publications found

Genes affected

SNED1 (HGNC:24696): (sushi, nidogen and EGF like domains 1) Predicted to enable Notch binding activity. Predicted to be involved in cell-matrix adhesion. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MTERF4 (HGNC:28785): (mitochondrial transcription termination factor 4) Enables rRNA binding activity. Predicted to be involved in rRNA processing and regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including mitochondrial transcription; protein targeting to mitochondrion; and ribosome assembly. Located in cytosol and mitochondrion. Part of mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10364306).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNED1	NM_001080437.3	MANE Select	c.3866G>T	p.Arg1289Leu	missense	Exon 27 of 32	NP_001073906.1
	MTERF4	NR_138463.2		n.5493C>A		non_coding_transcript_exon	Exon 7 of 7

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNED1	ENST00000310397.13	TSL:5 MANE Select	c.3866G>T	p.Arg1289Leu	missense	Exon 27 of 32	ENSP00000308893.8
	SNED1	ENST00000491761.1	TSL:1	n.1834G>T		non_coding_transcript_exon	Exon 2 of 2
	SNED1	ENST00000957411.1		c.3845G>T	p.Arg1282Leu	missense	Exon 27 of 32	ENSP00000627470.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000422 AC: 6 AN: 1421530 Hom.: 0 Cov.: 30 AF XY: 0.00000711 AC XY: 5 AN XY: 703272

African (AFR) AF: 0.00 AC: 0 AN: 32424

American (AMR) AF: 0.00 AC: 0 AN: 37924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25392

East Asian (EAS) AF: 0.00 AC: 0 AN: 37252

South Asian (SAS) AF: 0.0000497 AC: 4 AN: 80522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092962

Other (OTH) AF: 0.0000339 AC: 2 AN: 58972

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.25	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.41
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.013	D
Polyphen		0.37	B
Vest4		0.096
MutPred		0.37		Loss of phosphorylation at S1291 (P = 0.0574)
MVP		0.30
MPC		0.49
ClinPred		0.22	T
GERP RS		-1.4
Varity_R		0.081
gMVP		0.30
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6721345; hg19: chr2-242012729;